Istamycin A or B is an aminoglycosidic antibiotic which was discovered by the present inventors and is produced in the culture broth of Streptomyces tenjimariensis (see Japanese patent application prepublication "Kokai" No. 145697/80; UK patent Application publn. GB No. 2048855 A; and U.S. Pat. No. 4,296,106). 3-O-Demethylistamycin B is a new semi-synthetic aminoglycosidic antibiotic which was synthesized by us from istamycin B and exhibits a high antibacterial activity against a wide range of gram-negative and gram-positive bacteria, including Pseudomonas aeruginosa (see Japanese patent application No. 125334/80; EPC patent application publication No. 048,549 A; and U.S. patent application Ser. No. 241,649). 3-O-Demethylistamycin B is represented by the formula ##STR1##
It is known that a few of aminoglycosidic antibiotic substances are converted into an N-methanesulfonic acid derivative thereof by N-sulfomethylation of some or all of the amino group(s) present in the antibiotic molecule, and that the N-methanesulfonic acid derivative so produced exhibits a lower toxicity than the parent antibiotic. An example is N-methanesulfonic acid derivatives of kanamycin A (Journal of Antibiotics, A 14, page 170 (1961)). Besides, it has been found by the present inventors that an N-methanesulfonic acid derivative of 3',4'dideoxykanamycin B can be synthesized by interaction of 3', 4'-dideoxykanamycin B, an aldehyde and sulfurous acid or an alkali metal hydrogen sulfite, and that this N-methanesulfonic acid derivative is of lower toxicity than the parent 3',4'-dideoxykanamycin B and hence is valuable for therapeutic treatment of bacterial infections (see Japanese Patent Application "Kokai" No. 39653/77; UK Pat. No. 1507118; U.S. Pat. No. 4,091,202). It has also been found by us that an N-methanesulfonic acid derivative of istamycin A or B may be obtained as a new less toxic substance having useful antibacterial activity (see Japanese Patent Application prepublication "Kokai" No. 39653/77; UK patent application publn. GB No. 2083464 A; U.S. patent application Ser. No. 289,963).
Accordingly, if such a new antibiotic derivative of 3-O-demethylistamycin B which shows a lower toxicity than the parent 3-O-demethylistamycin B itself is provided, it will increase the applications of 3-O-demethylistamycin B.
An object of this invention is to provide a new antibiotic derivative of 3-O-demethylistamycin B which retains useful antibacterial activity of 3-O-demethylistamycin B but exhibits a lower toxicity than that of 3-O-demethylistamycin B. The outer object is to provide a process for the preparation of such new antibiotic derivative of 3-O-demethylistamycin B. Another objects of this invention will be clear from the following descriptions.
As a result of our research, we have now found that as new compounds, N-methanesulfonic acid derivatives of 3-O-demethylistamycin B can be synthesized by reaction of 3-O-demethylistamycin B of the above formula (I) or an acid addition salt thereof with an aldehyde of the formula: EQU RCHO (IV)
wherein R is as defined later and also with sulfurous acid or an alkali or alkaline earth metal hydrogen sulfite (including ammonium hydrogen sulfite) of the formula: EQU MHSO.sub.3 (V)
wherein M is a hydrogen atom, an alkali metal, alkaline earth metal atom or ammonium cation. We have confirmed that these N-methanesulfonic acid derivatives of 3-0-demethylistamycin B are remarkedly lower toxicity than 3-O-demethylistamycin B. 3-O-Demethylestamycin B contains three amino groups and one methylamino group per molecule as will be clear from the above formula (I), and it has been found that the new N-methanesulfonic acid derivative of 3-O-demethylistamycin B prepared is such one in which one, two, three or four groups of the aforesaid three amino groups and one methylamino group present in the molecule has or have been N-sulfomethylated, that is to say, substituted with a methanesulfonate group of the formula: EQU --CHRSP.sub.3 M (II)
wherein R is a hydrogen atom, an alkyl group, preferably an alkyl group of 1.about.4 carbon atoms, a substituted alkyl group, a phenyl group or a substituted phenyl group, and M represents a hydrogen atom, an ammonium cation, an alkali metal or an alkaline earth metal atom. The total number of the N-sulfomethylated amino and methylamino groups present in the resulting N-methanesulfonic acid derivative of 3-O-demethylistamycin B amounts to 1, 2, 3, or 4, depending upon the molar proportions of the aldehyde and the sulfurous acid or sulfite compound employed for 1 molar proportion of 3-O-demethylistamycin B.